Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate

ABSTRACT

Bacterial infections may be treated using a high dosage regimen of amoxycillin and potassium clavulanate. Preferably, the dosage is provided by a bilayer tablet

FIELD OF THE INVENTION

[0001] This invention relates to a novel method of treatment usingamoxycillin and potassium clavulanate and for novel formulations, inparticular tablet formulations, for use in such methods.

BACKGROUND OF THE INVENTION

[0002] Amoxycillin and potassium clavulanate are respectively a knownβ-lactam antibiotic and a known β-lactamase inhibitor. Productscomprising amoxycillin and potassium clavulanate are marketed under thetrade name “Augmentin” by SmithKline Beecham. Such products areparticularly effective for treatment of community acquired infections,in particular upper respiratory tract infections in adults and otitismedia in children.

[0003] Various tablet formulations of amoxycillin and potassiumclavulanate have been approved for marketing, comprising variousdifferent weights and ratios of amoxycillin and potassium clavulanate,for instance, conventional swallow tablets comprising 250/125, 500/125,500/62.5, and 875/125 mg amoxycillin/clavulanic acid (in the form ofpotassium clavulanate). Such tablets comprise amoxycillin and clavulanicacid in the ratio 2:1, 4:1, 8:1 and 7:1, respectively. The 875/125 mgtablet was developed to provide a tablet formulation which could beadministered in a bid (twice daily) dosage regimen It is also marketedfor tid (three times daily) dosing, in Italy and Spain. The 500/62.5 mgtablet was also developed to provide a tablet formulation which could beadministered in a bid dosage regimen, two such tablets being taken every12 h, in preference to a single 1000/125 mg tablet. A 1000/125 mg singledosage is also available, in France, but as a single dosage sachetrather than a tablet. Typically, the approved regimens provides a singledosage of 125 mg of potassium clavulanate.

[0004] In addition, WO 97/09042 (SmithKline Beecham) describes tabletformulations comprising amoxycillin and clavulanic acid in a ratio inthe range 12:1 to 20:1, preferably 14:1. Furthermore, it is suggestedthat the preferred dosage of 1 750/125 mg may be provided as twotablets, the first comprising 875/125 mg amoxycillin and clavulanic acidand the second 875 mg amoxycillin. The 14:1 ratio is said to be usefulfor the empiric treatment of bacterial infection potentially caused bydrug resistant S pneumoniae (DRSP). This patent application alsodescribes paediatric formulations comprising amoxycillin and clavulanatein a 14:1 ratio, for administering amoxycillin dosages of 90 mg/kg/day.Data suggest that such a dosage may provide antibiotic concentrationssufficient to eradicate DRSP with amoxycillin ± clavulanic acid MICs≦4μg/ml (Bottenfield et al, Pediatr Infect Dis J, 1998, 17, 963-8).

[0005] WO 94/16696 (SmithKline Beecham) discloses generally thatclavulanic acid may unexpectedly enhance the efficacy of amoxycillinagainst microorganisms having a resistant mechanism which is notβ-lactamase mediated.

[0006] Existing marketed tablet formulations of amoxycillin andpotassium clavulanate are conventional in that they provide immediaterelease of the active ingredients once the tablet reaches the stomach.There has also been some interest in developing formulations in whichthe release profile is modified, to allow for a longer interval betweendosages, for instances, every 12 hours (bid, q12 h), rather than every 8hours (tid, q8 h).

[0007] Thus, for instance, WO 95/20946 (SmithKline Beecham) describeslayered tablets comprising amoxycillin and, optionally, potassiumclavulanate, having a first layer which is an immediate release layerand a second layer which is a slow release layer. The broadest ratio ofamoxycillin to clavulanic acid is 30:1 to 1:1, with a preferred range of8:1 to 1:1. Amoxycillin is suitably in the form of amoxycillintrihydrate. Examples provided of such bilayered tablets have amoxycillintrihydrate in the immediate release layer and amoxycillin plusclavulanate in the slow release layer. Multi-layered tablets aredescribed more generically in WO 94/06416 (Jagotec AG). Furtherbilayered tablets comprising clavulanic acid and amoxycillin aredescribed in WO 98/05305 (Quadrant Holdings Ltd). In such tablets, afirst layer comprises amoxycillin and a second layer comprisesclavulanate and the excipient trehalose, to stabilise the clavulanatecomponent.

[0008] In addition, WO 95/28148 (SmithKline Beecham) describesamoxycillin/potassium clavulanate tablet formulations having a corecontaining amoxycillin and potassium clavulanate coated with a releaseretarding agent and surrounded by an outer casing layer of amoxycillinand potassium clavulanate. The release retarding agent is an entericcoating, so that there is an immediate release of the contents of theouter core, followed by a second phase from the core which is delayeduntil the core reaches the intestine. Furthermore, WO 96/04908(SmithKline Beecham) describes amoxycillin/potassium clavulanate tabletformulations which comprise amoxycillin and potassium clavulanate in amatrix, for immediate release, and granules in a delayed release formcomprising amoxycillin and potassium clavulanate. Such granules arecoated with an enteric coating, so release is delayed until the granulesreach the intestine. WO 96/04908 (SmithKline Beecham) describesamoxycillin/potassium clavulanate delayed or sustained releaseformulations formed from granules which have a core comprisingamoxycillin and potassium clavulanate, surrounded by a layer comprisingamoxycillin. WO 94/27557 (SmithKline Beecham) describes controlledrelease formulations of amoxycillin and clavulanic acid prepared using ahydrophobic waxy material which is then subjected to thermal infusion.

[0009] Controlled release formulations comprising amoxycillin have beendescribed by several groups. Thus, Arancibia et al ((Int J of Clin[Pharm, Ther and Tox, 1987, 25, 97-100) describe the pharmacokineticproperties and bioavailability of a controlled release formulationcomprising 500 mg of amoxycillin. No further details of the formulationare provided. The formulation was however designed to release 21 to 35%during the first 60 minutes, 51 to 66% at 4 hours, 70 to 80% at 6 hours,81 to 90% at 8 hours and more than 94% at 12 hours. They however foundlittle, if any, correlation between the in vitro dissolution rate andthe pharmacokinetic behaviour in the body. Hilton et al (InternationalJournal of Pharmaceutics, 1992, 86, 79-88) described an alternativecontrolled release tablet having a hydrophilic polymer matrix and a gasrelease system, to provide intragastric buoyancy, to enhance gastricretention time. This showed no advantage over a conventional capsuleformulation, with bioavailability being diminished. In contrast, Hiltonet al (Journal of Pharmaceutical Sciences, 1993, 82, 737-743) describeda 750 mg controlled release tablet incorporating the enteric polymerhydroxypropylmethyl cellulose acetate succinate. This however failed toshow any advantage over a conventional capsule. In particular, thebioavailability was reduced to 64.6% compared with the same dosageprovided in a capsule. More recently, Hoffman et al (Journal ofControlled Release, 1998, 54, 29-37 and WO 98/22091) have described atablet comprising 500 mg of amoxycillin in a matrix comprisinghydroxypropyl methyl cellulose, designed to release 50% of its contentsin the first three hours and complete the drug release process overeight hours. The time above MIC was found to be significantly extended,compared to a capsule formulation, but not enough for a 12 h dosinginterval. The discussion is in the context of a theoretical MIC of 0.2μg/ml.

[0010] It has therefore, been determined that there is a continuing needto provide new dosage regimens for amoxycillin/clavulanate which areeffective against more resistant bacteria.

SUMMARY OF THE INVENTION

[0011] The present invention relates to a method of treating bacterialinfections in humans which comprises administering thereto atherapeutically effective amount of amoxycillin and potassiumclavulanate such that the amount of amoxycillin is in the range 1900 to2600 mg and the amount of potassium clavulanate is such that the weightratio of amoxycillin to clavulanate is from about 2:1 to 20:1, an at adosage regiment/interval of about 12 hours. Suitably, the infection iscaused by the organisms S pneumoniae (including Drug Resistant andPenicillin Resistant S pneumoniae), H influenzae and/or M catarrhalis.

[0012] The present invention also relates to a modified releasepharmaceutical formulation comprising amoxycillin and potassiumclavulanate in the ratio from 2:1 to 20:1 in which all of the potassiumclavulanate and a first part of amoxycillin are formulated withpharmaceutically acceptable excipients which allow for immediate releaseof the potassium clavulanate and the first part of amoxycillin, to forman immediate release phase, and further comprising a second part ofamoxycillin formulated with pharmaceutically acceptable excipients whichallow for slow release of the second part of amoxycillin, to form a slowrelease phase.

[0013] The present invention also relates to an immediate releasepharmaceutical tablet formulation comprising 1000 mg ±5% amoxycillin and62.5 mg ±5% potassium clavulanate, in a nominal ratio of about 16:1, incombination with pharmaceutically acceptable excipients or carriers.

[0014] The present invention also relates to an immediate releasepharmaceutical formulation in the form of a single dose sachetcomprising 2000, 2250 or 2500 mg ±5% amoxycillin and 125 mg ±5%potassium clavulanate, in a nominal ratio of about 16:1, 18:1 or 20:1,respectively, or the corresponding half quantities thereof, incombination with pharmaceutically acceptable excipients or carriers.

[0015] Other suitable modified or immediate release formulations aredescribed herein in greater detail.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 shows the structure of various types of layered tablets ofthe present invention, in particular the structure of substantiallycylindrical compressed tablets are shown in longitudinal section. In

[0017]FIG. 1A, shows a tablet comprising a first layer (1) and a secondlayer (2), without any barrier layer or coating layer.

[0018]FIG. 1B, shows a tablet comprising a first layer (1), a secondlayer (2), and a barrier layer (3) sandwiched between the first andsecond layers (1) and (2).

[0019]FIG. 1C, shows a tablet comprising a first layer (1), a secondlayer (2), and a barrier layer (3) located on the end face of the secondlayer (2).

[0020]FIG. 1D, shows a tablet comprising a first layer (1), a secondlayer (2), a barrier layer (3) sandwiched between the first and secondlayers (1) and (2), and a coating layer (4) which partly covers thetablet. The dotted line shows the possibility of the coating layer (4A)covering the entire tablet.

[0021]FIG. 1E, shows a tablet comprising a first layer (1) a secondlayer (2), and a third layer (3) intermediate between the first andsecond layers (1) and (2). All three of these layers (1), (2) and (3)include active material content.

[0022]FIG. 2 demonstrates modified release tablets prepared according tothe process flow diagram shown in FIG. 2. In brief, immediate andmodified release blends are prepared which involve initial sieving andmilling, as indicated, before roller compaction in a Chilsonater andfurther milling, sieving and blending.

[0023]FIG. 3 demonstrates the dissolution profile for tablets ofExamples 1 and 2.

[0024]FIG. 4 demonstrate the pharmacokinetic profiles of Study A

[0025]FIG. 5 demonstrates the pharmacokinetic profile for amoxycillinplasma concentration for Study B (in which A is formulation V, B isformulation VI, D is formulation VIII).

DETAILED DESCRIPTION OF THE INVENTION

[0026] Part of the challenge in providing formulations of amoxycillin inwhich the drug release is effectively modified (and a ready explanationfor the lack of success in the studies already referenced) is therelatively narrow window for absorption of the drug in the smallintestine and the relatively short half life of the drug. Furthermore,the rapid elimination of amoxycillin (excretion half-life is 1.3 hours)makes it difficult to maintain serum levels as clearance from the bodyis very rapid.

[0027] In existing tablet formulations comprising amoxycillin andpotassium clavulanate, amoxycillin is present in the form amoxycillintrihydrate, as the use of this form provides tablets with greaterstorage stability than those in which amoxycillin is present as sodiumamoxycillin (see GB 2 005 538, Beecham Group Ltd). Sodium amoxycillin ishowever used as the amoxycillin component in existing formulations ofamoxycillin and potassium clavulanate adapted for IV administration. Theform of sodium amoxycillin used is a spray-dried form. In addition, EP 0131 147-A1 (Beecham Group plc) describes a further form of sodiumamoxycillin, so-called “crystalline sodium amoxycillin”. A furtherprocess for preparing salts of amoxycillin, including sodiumamoxycillin, is described in WO 99/62910 (SmithKline Beecham). Sodiumamoxycillin is relatively water soluble in comparison to amoxycillintrihydrate.

[0028] Formulations comprising clavulanic acid and a pharmaceuticallyacceptable organic acid or a salt-like derivative thereof, for examplecalcium citrate, have been described in WO 96/07408 (SmithKlineBeecham). In such formulations, it is postulated that the presence ofthe calcium citrate would help suppress the gastro-intestinalintolerance associated with oral dosing of clavulanate-containingproducts.

[0029] Furthermore, U.S. Pat. No. 5,051,262 (Elan Corp) describes theincorporation of an organic acid into a modified release formulation, toprovide a microenvironment in which the locally modified pH helps toprotect the active ingredient from degradation.

[0030] Of concern is the increasing resistance of pathogenic organisms,such as those found in respiratory tract infections, to anti-infectiveagents such as amoxycillin/potassium clavulanate, in particular drugresistant S pneumoniae. Increased resistance to penicillin ofSpneumoniae (due to modified penicillin binding proteins) is developingaround the world and is affecting clinical outcomes ( see for instanceApplebaum P C, Ped Inf Dis J, 1996, 15(10), 932-9). These penicillinresistant S pneumoniae (PRSP) have also been termed “DRSP” as they oftenexhibit decreased susceptibility not only to penicillin but also to awider range of antimicrobial classes, including macrolides, azalides,beta-lactams, sulfonamides and tetracyclines. Amoxycillin (with orwithout clavulanate), along with some of the newer quinolones, hasremained among the most active oral drugs against the increasinglyresistant isolates of S pneumoniae, based on both MIC levels andpharmacokinetic properties of these compounds. Resistance rates (andMICs) have however continued to increase. Penicillin resistance in S.pneumoniae can be assessed according to criteria developed by theNational Committee for Clinical Laboratory Standards (NCCLS), asfollows: susceptible strains have MICs of ≦0.06 μg/ml, intermediateresistance is defined as an MIC in the range 0.12 to 1.0 μg/ml whilstpenicillin resistance is defined as an MIC of ≧2 μg/ml. Furthermore, itis found that some 10% of pneumococci now have an amoxycillin MIC of 2μg/ml.

[0031] There is consequently a need to provide new formulations ofamoxycillin/clavulanate that combine the known safety profile and broadspectrum with improved activity against DRSP, including PRSP, withhigher MICs in empiric treatment of respiratory infections where Spneumoniae, H influenzae and M catarrhalis are likely pathogens.

[0032] For β-lactams, including amoxycillin, it is recognised that thetime above minimum inhibitory concentration (T>MIC) is thepharmacodynamic parameter most closely related to efficacy. For avariety of β-lactams, a bacteriological cure rate of 85 to 100% isachieved when serum concentrations exceed the MIC for more than about40% of the dosing interval (Craig and Andes, Ped Inf Dis J, 1996, 15,255-259). For a 12 hour dosing interval, this is about 4.8 hours.

[0033] A further parameter which may be of importance is the ratio ofthe maximum plasma concentration (Cmax) to the MIC value, as this may berelated to the potential to select for resistance. Too low a ratio mayencourage the development of resistant strains. Preferably, the plasmaC_(max) value is well above the MIC value, for instance, at least twotimes, more preferably at least three times, most preferably at leastfour times, the MIC value.

[0034] In a clinical study using the existing Augmentin 875/125 mgtablet, it was found that, when dosed at 12 hour intervals, the timeabove MIC was about 40% for an MIC of 2 μg/ml but only about 30% for anMIC of 4 μg/ml. The existing Augmentin 875/125 mg tablet has a C_(max)value of 11.6±2.8 μg/ml (Physicians Desk Reference, Medical EconomicsCo, 52 edition, 1998, 2802).

[0035] Based on the foregoing considerations, there is a continuing needto provide new dosage regimens for amoxycillin/clavulanate givingoptimised pharmacokinetic profiles for amoxycillin whilst notcompromising the bioavailability of clavulanate, so that therapy ismaximised, particularly against more resistant bacteria whilst the(further) development of resistance is minimised. It has now been foundthat such can be achieved using higher dosages of amoxycillin thanpreviously contemplated.

[0036] Accordingly, in a first aspect, the present invention providesfor a method of treating bacterial infections in humans which comprisesorally administering thereto a therapeutically effective amount ofamoxycillin and potassium clavulanate such that the amount ofamoxycillin is in the range 1900 to 2600 mg, preferably 1950 to 2550 mg,and the amount of potassium clavulanate is such that the weight ratio ofamoxycillin to clavulanate is from 2:1 to 20:1, preferably 7:1 to 20:1,more preferably 14:1 to 20:1, at intervals of about 12 hours(hereinafter “h”).

[0037] Preferably, the dosage regimen provides a mean plasmaconcentration of amoxycillin of 4 μg/mL for at least 4.4 h, preferablyat least 4.6 h, more preferably at least 4.8 h, most preferably forabout 6 h or longer.

[0038] More preferably, the dosage regimen provides a mean plasmaconcentration of amoxycillin of 8 μg/ml for at least 4.4 h, morepreferably at least 4.6 h, most preferably at least 4.8 h.

[0039] Preferably, the dosage regimen provides a mean maximum plasmaconcentration (C_(max)) of amoxycillin which is at least 8 μg/mL,preferably at least 12 μg/mL, yet more preferably at least 14 μg/mL,most preferably at least 16 μg/mL.

[0040] Preferably, the mean plasma concentration of amoxycillin and themean maximum plasma concentration of amoxycillin are measured after oraladministration of a formulation comprising amoxycillin at the start of alight meal.

[0041] In a further aspect, the present invention provides for a methodof treating bacterial infections in humans which comprises administeringthereto a therapeutically effective amount of amoxycillin and potassiumclavulanate such that the amount of amoxycillin is in the range 1400 to1900 mg, preferably 1500 to 1900 mg, and the amount of potassiumclavulanate is such that the weight ratio of amoxycillin to clavulanateis from 2:1 to 14:1, preferably 7:1 to 14:1, more preferably 12:1 to14:1, at intervals of about 12 h, such that the dosage regimen providesa mean plasma concentration of amoxycillin of 4 μg/mL for at least 4.4h, preferably at least 4.6 h, more preferably at least 4.8 h, mostpreferably for about 6 h or longer; more preferably, a mean plasmaconcentration of amoxycillin of 8 μg/ml for at least 4.4 h, morepreferably at least 4.6 h, most preferably at least 4.8 h, and a meanmaximum plasma concentration (C_(max)) of amoxycillin which is at least8 μg/mL, preferably at least 12 μg/mL, yet more preferably at least 14μg/mL, most preferably at least 16 μg/mL.

[0042] Bacterial infections amenable to the present invention includeinfections caused by the organisms S pneumoniae (including DrugResistant S pneumoniae (DRSP), for instance Penicillin Resistant Spneumoniae (PRSP)), and/or the β-lactamase producing respiratorypathogens, most notably H influenzae and M catarrhalis, such asrespiratory tract infections, including community acquired pneumoniae(CAP), acute exacerbations of chronic bronchitis (AECB) and acutebacterial sinusitis (ABS), where the higher break points achievablethrough the improved pharmacokinetic profile will be especiallyadvantageous compared to existing antibacterial agents. Most outpatientrespiratory infections are caused by either S pneumoniae and/or theβ-lactamase producing bacteria and are treated empirically so there is acontinuing need for a method of treatment, such as the presentinvention, that provides a spectrum of activity that covers all suchpathogens. The duration of therapy will generally between 7 and 14 days,typically 7 days for indications such as acute exacerbations of chronicbronchitis but 10 days for acute bacterial sinusitis. Typically, thedosages regimens are designed for adult patients, rather than paediatricpatients.

[0043] The term “amoxycillin” is used generically to refer toamoxycillin or an alkaline salt thereof, in particular amoxycillintrihydrate and (crystallised) sodium amoxycillin, without distinctionand unless otherwise indicated.

[0044] Unless otherwise indicated, weights of amoxycillin and(potassium) clavulanate refer to the equivalent weights of thecorresponding free acids. In addition, it will be appreciated that inpractice, weights of amoxycillin and clavulanate to be incorporated intoa formulation will be further adjusted, in accord with conventionalpractice, to take account of the potency of the amoxycillin andclavulanate.

[0045] In a first embodiment, a dosage of amoxycillin of from 1900 to2600 mg and a corresponding amount of potassium clavulanate maydelivered from an immediate release formulation. Accordingly, in afurther aspect, the present invention provides for method of treatingbacterial infections in humans which comprises administering thereto atherapeutically effective amount of amoxycillin and potassiumclavulanate such that the amount of amoxycillin is in the range 1900 to2600, preferably 1950 to 2550 mg, and the amount of potassiumclavulanate is such that the weight ratio of amoxycillin to clavulanateis from 2:1 to 20:1, preferably 7:1 to 20:1, more preferably 14:1 to20:1, at intervals of about 12 h, wherein the dosage is delivered froman immediate formulation.

[0046] As used herein, the term “immediate release” refers to therelease of the majority of the active material content within arelatively short time, for example within 1 hour, preferably within 30minutes, after oral ingestion. Examples of such immediate releaseformulations include conventional swallow tablets, dispersible tablets,chewable tablets, single dose sachets and capsules.

[0047] Representative dosages include 2000/125, 2250/125 and 2500/125 mgof amoxycillin and potassium clavulanate, respectively. A preferreddosage is 2000/125 mg of amoxycillin and potassium clavulanate.

[0048] The dosage in an immediate release formulation may be provided asa single tablet, for instance a dispersible tablet, a chewable tabletwhich may also be, effervescent and/or dispersible, a single dosecapsule or a single dosage sachet, comprising, for instance, 2000, 2250or 2500 mg amoxycillin and 125 mg potassium clavulanate. Alternatively,the dosage may be made up of a number of smaller tablets or capsules,for instance, 2, 3 or 4, some of which may be the same and some of whichmay comprise amoxycillin only and no potassium clavulanate.Representative such smaller tablets include swallow tablets, dispersibletablets and chewable tablets which may also be effervescent and/ordispersible. Thus, for instance, a dosage of 2000 mg amoxycillin and 125mg potassium clavulanate may be provided by a combination of threetablets each comprising 500 mg amoxycillin and one tablet comprising 500mg amoxycillin and 125 mg potassium clavulanate. Alternatively, such adosage may be provided by two tablets each comprising 1000/62.5 mgamoxycillin/potassium clavulanate. In addition, a dosage of 2250 mgamoxycillin and 125 mg potassium clavulanate may be provided by acombination of four tablets comprising 500 mg amoxycillin and one tabletcomprising 250 mg amoxycillin and 125 mg potassium clavulanate or twotablets comprising 875 mg amoxycillin and one tablet comprising 500 mgamoxycillin and 125 mg potassium clavulanate. Furthermore, a dosage of2500 mg amoxycillin and 125 mg potassium clavulanate may be provided bya combination of four tablet comprising 500 mg amoxycillin and onetablet comprising 500 mg amoxycillin and 125 mg potassium clavulanate.Tablets comprising 500 and 875 mg amoxycillin and 250/125, 500/125 and875/125 mg amoxycillin/potassium clavulanate are already commerciallyavailable.

[0049] It will be appreciated that immediate release tablets comprising1000/62.5 mg are novel. Accordingly, in a further aspect, the presentinvention provides for an immediate release pharmaceutical tabletformulation comprising 1000 mg ±5% amoxycillin and 62.5 mg ±5% potassiumclavulanate, in a nominal ratio of about 16:1, in combination withpharmaceutically acceptable excipients or carriers. Immediate releasetablets comprising 1000/62.5 mg can be readily prepared by adaptingcompositions previously described for 875/125 and 1000/125 mg tablets(see for instance, WO 95/28927 and WO 98/35672, SmithKline Beecham).

[0050] It will also be appreciated that immediate release single dosagesachets comprising 2000/125 mg, 2250/125 mg or 2500/125 mg, or thecorresponding half quantities thereof, are novel. Accordingly, in afurther aspect, the present invention provides for an immediate releasepharmaceutical formulation in the form of a single dose sachetcomprising 2000, 2250 or 2500 mg ±5% amoxycillin and 125 mg ±5%potassium clavulanate, in a nominal ratio of about 16:1, 18:1 or 20:1,respectively, or the corresponding half quantities thereof, incombination with pharmaceutically acceptable excipients or carriers.Such sachets can be readily prepared by adapting compositions previouslydescribed for 875/125 and 1000/125 mg sachets (see for instance, WO92/19277 and WO 98/35672, SmithKline Beecham).

[0051] It will be further appreciated that immediate release chewabletablets comprising 2000, 2250 or 2500/125 mg are novel. Accordingly, ina further aspect, the present invention provides for an immediaterelease pharmaceutical formulation in the form of a chewable, optionallyeffervescent, tablet comprising 2000, 2250, or 2500 mg amoxycillin and125 mg ±5% potassium clavulanate, in a nominal ratio of about 16:1, 18:1or 20:1, respectively, or the corresponding half quantities thereof, incombination with a chewable base and, if effervescent, an effervescentcouple, and other pharmaceutically acceptable excipients or carriers.Such chewable tablets can be readily prepared by adapting compositionspreviously described for chewable tablets comprising amoxycillin andpotassium clavulanate (see for instance, EP-A-0 396 335, Beecham Groupand WO 98/35672, SmithKline Beecham).

[0052] In a second embodiment, a dosage of amoxycillin of from 1900 to2600 mg and a corresponding amount of potassium clavulanate may bedelivered from a modified release formulation. Accordingly, in a furtheraspect, the present invention provides for method of treating bacterialinfections in humans which comprises administering thereto atherapeutically effective amount of amoxycillin and potassiumclavulanate such that the amount of amoxycillin is in the range 1900 to2600 mg, preferably 1950 to 2550 mg, and potassium clavulanate ispresent in a pro rata amount such that the weight ratio of amoxycillinto potassium clavulanate is from 2:1 to 20:1, preferably 7:1 to 20:1,more preferably 14:1 to 20:1, at intervals of about 12 h, in which thedosage is delivered from a modified release formulation.

[0053] In a third embodiment, a dosage of amoxycillin of from 1400 to1900 mg and a corresponding amount of clavulanate may be delivered fromthe modified release formulation. Accordingly, in a further aspect, thepresent invention provides for method of treating bacterial infectionsin humans which comprises administering thereto a therapeuticallyeffective amount of amoxycillin and potassium clavulanate such that theamount of amoxycillin is in the range 1400 to 1900 mg, preferably 1500to 1900 mg, and potassium clavulanate is present in a pro rata amountsuch that the weight ratio of amoxycillin to clavulanate is from 2:1 to14:1, preferably 7:1 to 14:1, more preferably 12:1 to 14:1, at intervalsof about 12 h, in which the dosage is delivered from a modified releaseformulation.

[0054] As used herein, the term “modified release” refers to a releaseof drug substance from a pharmaceutical formulation which is at a slowerrate than from an immediate release formulation such as a conventionalswallow tablet or capsule and may include an immediate release phase anda slow release phase. Modified release formulations are well known inthe art, see for instance Remington: The Science and Practice ofPharmacy, Nineteenth Edn, 1995, Mack Publishing Co, Pennsylvania, USA.

[0055] Preferably, the modified release formulations of the presentinvention are formulated such that the release of amoxycillin iseffected predominantly through the stomach and small intestine, so thatabsorption through the specific amoxycillin absorption site in the smallintestine is maximised. Preferably, the amoxycillin release profile ismade up of a contribution from an immediate release component which isthen complemented and extended by an on-going contribution from a slowrelease component. Preferably, potassium clavulanate is releasedsubstantially immediately from the formulation, when the formulationreaches the stomach and is absorbed therefrom, thereby minimising therisk of degradation from prolonged exposure to the stomach. Suchformulations are preferably formulated such that the release ofamoxycillin and potassium clavulanate occurs predominantly within 3hours of ingestion of the formulation.

[0056] Typically, a dosage will provide 125 mg of potassium clavulanate,the amount approved in existing regimens where a lesser amount ofamoxycillin is administered.

[0057] Representative modified release dosages include 1500/125,1750/125 and 2000/125 mg of amoxycillin and potassium clavulanate,respectively. A preferred dosage is 2000/125 mg of amoxycillin andpotassium clavulanate.

[0058] The dosage in a modified release formulation may conveniently beprovided as a number of swallow tablets or capsules, for instance two,three or four, some of which may be the same and some of which maycomprise amoxycillin only and no potassium clavulanate. Thus, forinstance, a dosage of 2000 mg amoxycillin and 125 mg potassiumclavulanate may be provided by two tablets each comprising 1000/62.5 mgamoxycillin/potassium clavulanate, one tablet comprising 1000 mg ofamoxycillin and one tablet comprising 1000/125 mg amoxycillin/potassiumclavulanate, two tablets each comprising 500 mg amoxycillin and onetablet comprising 1000/125 mg amoxycillin/potassium clavulanate or fourtablets each comprising tablet 500/32.25 mg amoxycillin/potassiumclavulanate. In addition, a dosage of 1750 mg amoxycillin and 125 mgpotassium clavulanate may be provided by two tablets each comprising875/62.5 mg amoxycillin/potassium clavulanate or one tablet comprising875 mg of amoxycillin and one tablet comprising 875/125 mgamoxycillin/potassium clavulanate. A preferred tablet comprises1000/62.5 mg amoxycillin/potassium clavulanate.

[0059] The dosage in an modified release formulation may be may alsoprovided as a single tablet. Because of the quantities of drug substancebeing used, this would preferably be other than a swallow tablet, forinstance a dispersible tablet or a chewable tablet which may also beeffervescent and/or dispersible or a dispersible tablet. A single unitdosage may also be conveniently provided as a single dosage sachet. Itwill be appreciated that the dosage may also be provided as a number ofsmaller non-swallow tablets or sachets, for instance 2×1000/62.5 mg or4×500/32.25 mg amoxycillin/potassium clavulanate.

[0060] Preferably, in the modified release formulation, all thepotassium clavulanate is provided in an immediate release phase whilstamoxycillin is provided in both an immediate release and a slow releasephase.

[0061] Accordingly, in a further aspect, the present invention providesfor a modified release pharmaceutical formulation comprising amoxycillinand potassium clavulanate in the ratio from 2:1 to 20:1, preferably 7:1to 20:1, more preferably 12:1 to 20:1, most preferably 14:1 to 16:1 inwhich all of the potassium clavulanate and a first part of amoxycillinare formulated with pharmaceutically acceptable excipients which allowfor immediate release of the potassium clavulanate and the first part ofamoxycillin, to form an immediate release phase, and further comprisinga second part of amoxycillin formulated with pharmaceutically acceptableexcipients which allow for slow release of the second part ofamoxycillin, to form a slow release phase.

[0062] As used herein, the term “slow release” refers to the gradual butcontinuous or sustained release over a relatively extended period of theactive material content (in this case amoxycillin) after oral ingestionand which starts when the formulation reaches the stomach and starts todisintegrate/dissolve. The release will continue over a period of timeand may continue through until and after the formulation reaches theintestine. This can be contrasted with the term “delayed release” inwhich release of the active does not start immediately the formulationreaches the stomach but is delayed for a period of time, for instanceuntil when the formulation reaches the intestine when the increasing pHis used to trigger release of the active from the formulation.

[0063] Preferably, the modified release formulation has an in vitrodissolution profile in which 45 to 65%, preferably 45 to 55% of theamoxycillin content is dissolved within 30 min; further in which 50 to75%, preferably 55 to 65% of the amoxycillin content is dissolved within60 min; further in which 55 to 85%, preferably 60 to 70% of theamoxycillin content is dissolved within 120 min; further in which 70 to95%, preferably 75 to 85% of the amoxycillin content is dissolved within180 min; and further in which 70 to 100%, preferably 75 to 100% of theamoxycillin content is dissolved within 240 min. In comparison, aconventional, immediate release amoxycillin tablet dissolves essentiallycompletely within 30 minutes. The dissolution profile may be measured ina standard dissolution assay, for instance <711> Dissolution Test,Apparatus 2, provided in USP 23, 1995, at 37.0±0.5° C., using deionisedwater (900 mL) and a paddle speed of 75 rpm.

[0064] Preferably, the modified release formulation has a biphasicprofile in vivo with respect to amoxycillin, that is an initial burstfrom the immediate release phase to provide an acceptable C_(max) value,supplemented by a further contribution from the slow release phase, toextend the T>MIC parameter to an acceptable value.

[0065] Preferably, the modified formulation provides an “Area Under theCurve” (AUC) value which is substantially similar to, for instance atleast 80%, preferably at least 90%, more preferably about 100%, of thatof the corresponding dosage of amoxycillin taken as a conventional(immediate release) formulation, over the same dosage period, therebymaximising the absorption of the amoxycillin component from the slowrelease component.

[0066] The pharmcokinetic profile for a dosage of the present inventionmay be readily determined from a single dosage bioavailability study inhuman volunteers. Plasma concentrations of amoxycillin may then bereadily determined in blood samples taken from patients according toprocedures well known and documented in the art.

[0067] Representative modified release formulations include a tablet,including swallow tablets, dispersible tablets, chewable tablets whichmay also be effervescent and/or dispersible and, a capsule, granules ora sachet, typically a swallow tablet.

[0068] Representative modified release formulations having an immediateand a slow release phase provide a unit dosage in the range 700 to 1300mg, preferably, 950 to 1300 mg, amoxycillin, for instance unit dosagesof 1000, 875 and 750/62.5 mg amoxycillin/clavulanate. Alternatively, andwhere the physical size of the dosage form is not a problem, the unitdosage may provide the whole dosage, for instance a single dosagesachet, chewable tablet or dispersible tablet may comprise 1400 to 2600mg, preferably, 1900 to 2600 mg, amoxycillin, for instance unit dosagesof 2000, 1750 and 1500/125 mg amoxycillin/clavulanate. It will beappreciated that such 1000, 875 and 750/62.5 mg formulations are novel.

[0069] Accordingly, in a further aspect, the present invention providesfor a pharmaceutical formulation having an immediate release phase and aslow release phase and comprising:

[0070] (a) a unit dosage in the range 700 to 1300 mg, preferably, 950 to1300 mg, amoxycillin, and a corresponding amount of potassiumclavulanate, in a nominal ratio of about 16:1, 14;1 or 12:1, forinstance unit dosages of 1000, 875 or 750 mg ±5% amoxycillin and 62.5 mg±5% potassium clavulanate, respectively, or

[0071] (b) a unit dosage in the range 1400 to 2600 mg, preferably, 1900to 2600 mg, amoxycillin, and a corresponding amount of potassiumclavulanate, in a nominal ratio of about 16:1, 14;1 or 12:1, forinstance unit dosages of 2000, 1750 or 1500 mg ±5% amoxycillin and 62.5mg ±5% potassium clavulanate, respectively, in combination withpharmaceutically acceptable excipients or carriers.

[0072] Preferably, the ratio of amoxycillin in the immediate and slowrelease phases is from 3:1 to 1:3, more preferably, from 2:1 to 2:3, yetmore preferably 3:2 to 1:1. Representative ratios include about 2:1, 9:7or 1:1. It is found useful to employ an excess of amoxycillin in theimmediate release phase, to ensure an adequate C_(max) value.

[0073] In the modified release formulations of the present invention,the portion of amoxycillin which is released immediately may be providedas amoxycillin trihydrate or an alkaline salt thereof, for instancepotassium or sodium amoxycillin, preferably, (crystallised) sodiumamoxycillin or a mixture thereof, preferably amoxycillin trihydrate;while the portion of amoxycillin which is released slowly is provided asamoxycillin trihydrate or an alkaline salt thereof, for instancepotassium or (crystallised) sodium amoxycillin or a mixture thereof,preferably (crystallised) sodium amoxycillin.

[0074] Preferably, the modified release formulation is a tablet. In apreferred modified release tablet comprising 1000 mg amoxycillin and62.5 mg potassium clavulanate, the immediate release phase comprisesabout 563 mg ±5% amoxycillin trihydrate and about 62.5 mg ±5% ofpotassium clavulanate and the slow release phase about 438 mg ±5% ofamoxycillin, preferably as (crystallised) sodium amoxycillin.

[0075] In a representative modified release tablet of the presentinvention, the immediate release phase comprises about 438 mgamoxycillin, preferably amoxycillin trihydrate and about 62.5 mg ofpotassium clavulanate and the slow release phase about 438 mg ofamoxycillin, preferably (crystallised) sodium amoxycillin, providingoverall an 875/62.5 mg (14:1) tablet.

[0076] In a further representative tablet of the present invention, theimmediate release phase comprises about 500 mg amoxycillin and about62.5 mg of potassium clavulanate and the slow release phase about 250 mgof amoxycillin, preferably (crystallised) sodium amoxycillin, providingoverall a 750/62.5 mg (12:1) tablet.

[0077] It will be appreciated that the use of a mixture of amoxycillintrihydrate and sodium amoxycillin is more generally applicable to otherpharmaceutical formulations comprising amoxycillin and potassiumclavulanate.

[0078] Accordingly, in a further aspect, the present invention providesfor a pharmaceutical formulation comprising amoxycillin and potassiumclavulanate in a ratio of from 1:1 to 30:1,preferably2:1 to 20:1, morepreferably 12:1 to 20:1, yet more preferably 14:1 to 16:1, in whichamoxycillin is provided as a mixture of amoxycillin trihydrate andsodium amoxycillin in a ratio of from 3:1 to 1:3, more preferably from2:1 to 2:3, yet more preferably 3:2 to 1:1. Preferably, sodiumamoxycillin is crystallised sodium amoxycillin. Representativeformulation types include tablets, including immediate release andmodified release tablets as herein described, as well as other soliddosage forms such as capsules, single dosage sachets and granules.Representative tablets include those comprising 1000, 875, 500 and 250mg amoxycillin and a corresponding weight of potassium clavulanate.Representative ratios include 4:1, 7:1, 8:1, 14:1, and 16:1 (amoxycillin:clavulanate). Preferably, in modified release formulations of thepresent invention, the amoxycillin in the immediate release phaseconsists essentially of amoxycillin trihydrate and the amoxycillin ofthe slow release phase consists essentially of sodium amoxycillin.

[0079] For a tablet formulation, the immediate and slow release phasesmay be provided in a number of different formats.

[0080] In a preferred aspect, the immediate and slow release phases areprovided as separate layers of a layered tablet.

[0081] Accordingly, in a further aspect, the present invention providesfor a layered tablet formulation comprising potassium clavulanate andamoxycillin in an immediate release layer phase and amoxycillin in aslow release layer. The layered tablet may have two layers, or twolayers plus one or more barrier layer, as well as a coating layer. Asused herein, the term “bilayer” tablet refers to a tablet consisting ofan immediate release and a slow release layer, optionally with a coatinglayer.

[0082] An immediate release layer may be, for example, a layer whichdisintegrates immediately or rapidly and has a composition similar tothat of known tablets which disintegrate immediately or rapidly. Forexample, the layer may comprise, in addition to the active materialcontent, excipients including diluents such as microcrystallinecellulose; disintegrants such as cross-linked polyvinylpyrrolidone(CLPVP), sodium starch glycollate; compression aids such as colloidalsilicon dioxide and microcrystalline cellulose; and lubricants such asmagnesium stearate. Such an immediate release layer may comprise around60 to 85% (all percentages given herein are on a weight percentage basisunless otherwise stated), preferably 70 to 85%, of active materialcontent, around 10 to 30%, preferably 10 to 20% of fillers/compressionaids, and conventional amounts of disintegrants and lubricants,typically about 0.5 to 3%, etc.

[0083] An alternative type of immediate release layer may be a swellablelayer having a composition which incorporates polymeric materials whichswell immediately and extensively in contact with water or aqueousmedia, to form a water permeable but relatively large swollen mass.Active material content may be immediately leached out of this mass.

[0084] Slow release layers have a composition which comprisesamoxycillin together with a release retarding excipient which allows forslow release of amoxycillin. Suitable release retarding excipientsinclude pH sensitive polymers, for instance polymers based uponmethacrylic acid copolymers such as the Eudragit (trade mark) polymers,for example Eudragit L (trade mark) which may be used either alone orwith a plasticiser; release-retarding polymers which have a high degreeof swelling in contact with water or aqueous media such as the stomachcontents; polymeric materials which form a gel on contact with water oraqueous media; and polymeric materials which have both swelling andgelling characteristics in contact with water or aqueous media.

[0085] Release retarding polymers which have a high degree of swellinginclude, inter alia, cross-linked sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, high-molecular weighthydroxypropylmethylcellulose, carboxymethylamide, potassiummethacrylatedivinylbenzene co-polymer, polymethylmethacrylate,cross-linked polyvinylpyrrolidone, high-molecular weightpolyvinylalcohols etc.

[0086] Release retarding gellable polymers include methylcellulose,carboxymethylcellulose, low-molecular weighthydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols,polyoxyethyleneglycols, non-cross linked polyvinylpyrrolidone, xanthangum etc.

[0087] Release retarding polymers simultaneously possessing swelling andgelling properties include medium-viscosity hydroxypropylmethylcelluloseand medium-viscosity polyvinylalcohols.

[0088] A preferred release-retarding polymer is xanthan gum, inparticular a fine mesh grade of xanthan gum, preferably pharmaceuticalgrade xanthan gum, 200 mesh, for instance the product Xantural 75 (alsoknown as Keltrol CR, Trade Mark, Monsanto, 800 N Lindbergh Blvd, StLouis, Mo. 63167, USA). Xanthan gum is a polysaccharide which uponhydration forms a viscous gel layer around the tablet through which theactive has to diffuse. It has been shown that the smaller the particlesize, the slower the release rate. In addition, the rate of release ofdrug substance is dependent upon the amount of xanthan gum used and canbe adjusted to give the desired profile. Controlled release formulationscomprising from 7.5 to 25% xanthan gum are described in EP 0 234 670-A(Boots Co plc). The preferred embodiment is a tablet comprisingibuprofen as the drug substance and 15-20% xanthan gum, which is takenonce daily.

[0089] Examples of other polymers which may be used include Methocel K4M(Trade Mark), Methocel E5 (Trade Mark), Methocel E50 (Trade Mark),Methocel E4M (Trade Mark), Methocel K15M (Trade Mark) and Methocel K100M(Trade Mark). An example of a suitable polymer mixture is a mixture ofMethocel E5 and K4M, for example 1:1, w:w.

[0090] Other known release-retarding polymers which may be incorporatedinclude hydrocolloids such as natural or synthetic gums, cellulosederivatives other than those listed above, carbohydrate-based substancessuch as acacia, gum tragacanth, locust bean gum, guar gum, agar, pectin,carageenin, soluble and insoluble alginates, carboxypolymethylene,casein, zein, and the like, and proteinaceous substances such asgelatin.

[0091] Such a slow release layer may contain polymers which immediatelyswell in contact with water or aqueous media so that they form arelatively large swollen mass which is not immediately discharged fromthe stomach into the intestine.

[0092] The slow release layer may also include diluents such as lactose;compression aids such as microcrystalline cellulose; and lubricants suchas magnesium stearate. The slow release layer may further comprisedisintegrants, such as cross-linked polyvinylpyrrolidone (CLPVP) andsodium starch glycollate; binders such as povidone(polyvinylpyrrolidone); desiccants, such as silicon dioxide; and solubleexcipients such as mannitol or other soluble sugars. Typically, the slowrelease layer comprises from about 60 to 80% by weight of amoxycillin;from 10 to 20% by weight of diluent/compression aid and from 1 to 2.5%by weight of lubricant.

[0093] When xanthan gum is used as release-retarding polymer, the layercontains from 60 to 80% of amoxycillin, from 1 to 25%, preferably 2 to15%, more preferably 4 to 15% of xanthan gum, from 10 to 30%, preferably10 to 20% of fillers/compression aids, and conventional quantities oflubricants, all % being by weight of the layer. In a preferredembodiment, the slow release layer comprises from 70 to 80% ofamoxycillin, from 4 to 10%, of xanthan gum, from 10 to 20% ofmicrocrystalline cellulose, and from 1 to 2.5% of magnesium stearate,all % being by weight of the layer.

[0094] When release-retarding polymers other than xanthan gum are used,the slow release layer may contain around 30 to 70%, preferably from 40to 60%, of amoxycillin, from 15 to 45% of release-retarding polymer,from 0 to 30% of fillers/compression aids, conventional quantities oflubricants, and from 5 to 20% of soluble excipients, all % being byweight of the layer.

[0095] It has also been surprisingly found that when the amoxycillin inthe slow release layer is in the form of a soluble salt thereof, such assodium amoxycillin, then the release thereof may be retarded by theinclusion of an organic acid.

[0096] Accordingly, in a further aspect, the present invention providesfor the use of a pharmaceutically acceptable organic acid as a releaseretarding excipient in a formulation comprising a pharmaceuticallyacceptable soluble salt of amoxycillin, for instance sodium or potassiumamoxycillin, preferably sodium amoxycillin.

[0097] It will be appreciated that the use of an organic acid as arelease retarding excipient is more generally applicable beyond theparticular formulations hereinbefore described.

[0098] Accordingly, the present invention further provides for apharmaceutical formulation comprising a pharmaceutically acceptablesoluble salt of amoxycillin, for instance sodium amoxycillin, in a slowrelease phase which further comprises a release retarding excipientwhich is a pharmaceutically acceptable organic acid present in a molarratio of from 100:1 to 1:10,preferably50:1 to 1:5, more preferably 20:1to 1:2 (amoxycillin to organic acid).

[0099] It is believed that intimate contact between the organic acid andthe salt of amoxycillin in the pharmaceutical formulation, for instanceas a consequence of compacted granule formation or direct compression ina tablet, causes some form of interaction which modifies the release ofthe amoxycillin component from the formulation.

[0100] Soluble pharmaceutically acceptable salts of amoxycillin includealkali metal salts such as sodium and potassium; alkaline earth metalsalts such as magnesium and calcium, and acid salts such as amoxycillinhydrochloride. Preferably, the salt is sodium amoxycillin, morepreferably crystalline sodium amoxycillin.

[0101] As used herein, the term “pharmaceutically acceptable organicacid” refers to organic acids which are without pharmacological effectper se, have acceptable organoleptic properties, have acceptabledensity, do not have an extreme pH and are preferably solid. Examplesthereof include mono-carboxylic acids and poly-carboxylic acids havingfrom 2 to 25, preferably from 2 to 10, carbon atoms; monocyclic andpolycyclic aryl acids such as benzoic acid; as well as monohydrogen,dihydrogen etc metal salts of multi-valent acids. A singlepharmaceutically acceptable organic acid may be used, or two or more ofsuch may be used in combination. Preferably, the organic acid is aC₍₂₋₁₀₎alkyl- or alkenyl- carboxylic acid having from one, two or threecarboxylic acid groups, and optionally with one or more hydroxysubstituents or an additional CO group in the carbon chain, for instancemalonic acid, succinic acid, fumaric acid, maleic acid, adipic acid,lactic acid, levulinic acid, sorbic acid or a fruit acid such astartaric acid, malic acid, ascorbic acid or citric acid, or an acidicsalt thereof, more preferably citric acid.

[0102] The organic acid may be used alone or in combination with arelease retarding polymer as hereinbefore described. A preferredcombination comprises citric acid and a release retarding gellablepolymer, in particular xanthan gum. In the presence of the organic acid,for instance citric acid, xanthan gum may be used at a lower level thenwhen included on its own, for instance, from 0.5 to 8%, preferably 1 to5%, typically about 2%, by weight of the slow release layer.

[0103] When an organic acid is used as a release-retarding excipient,the slow release layer contains from 60 to 80% of a soluble salt ofamoxycillin, from 10 to 30%, preferably 10 to 20% of fillers/compressionaids, and conventional quantities of lubricants, all % being by weightof the layer. In a preferred embodiment, the slow release layercomprises from 60 to 70% of a soluble salt of amoxycillin, from 10 to20% of microcrystalline cellulose, and from 1 to 2.5% of magnesiumstearate, all % being by weight of the layer.

[0104] In a representative example, a layered tablet comprises in theslow release layer crystallised sodium amoxycillin and citric acid, in amolar ratio of about 50:1 to 1:2, preferably 20:1 to 1:2, morepreferably 2:1 to 1:1.2, yet more preferably about 1:1. In a preferredembodiment, the slow release layer comprises about 438 mg ±5%crystallised sodium amoxycillin, about 78 mg ±10% citric acid and about2% by weight of xanthan gum.

[0105] In a preferred layered tablet comprising 1000 mg amoxycillin and62.5 mg potassium clavulanate, the immediate release layer comprisesabout 563 mg ±5% amoxycillin, preferably amoxycillin trihydrate, andabout 62.5 mg ±5% of potassium clavulanate and the slow release layerabout 438 mg ±5% of amoxycillin, preferably crystallised sodiumamoxycillin, about 78 mg ±10% citric acid and about 2% by weight ofxanthan gum.

[0106] The tablet formulations of the invention may also include one ormore barrier layers, which may be located between the respective firstand second layers, and/or on one or more of the outer surfaces of thefirst and second layers, for example the end faces of the layers of asubstantially cylindrical tablet. Such barrier layers may, for example,be composed of polymers which are either substantially or completelyimpermeable to water or aqueous media, or are slowly erodable in wateror aqueous media or biological liquids and/or which swell in contactwith water or aqueous media. Suitably the barrier layer should be suchthat it retains these characteristics at least until complete orsubstantially complete transfer of the active material content to thesurrounding medium.

[0107] Suitable polymers for the barrier layer include acrylates,methacrylates, copolymers of acrylic acid, celluloses and derivativesthereof such as ethylcelluloses, cellulose acetate propionate,polyethylenes and polyvinyl alcohols etc. Barrier layers comprisingpolymers which swell in contact with water or aqueous media may swell tosuch an extent that the swollen layer forms a relatively large swollenmass, the size of which delays its immediate discharge from the stomachinto the intestine. The barrier layer may itself contain active materialcontent, for example the barrier layer may be a slow or delayed releaselayer. Barrier layers may typically have an individual thickness of 2 mmto 10 microns.

[0108] Suitable polymers for barrier layers which are relativelyimpermeable to water include the Methocel (trade mark) series ofpolymers mentioned above, for example Methocel K100M, Methocel K15M,Methocel E5 and Methocel E50, used singly or combined, or optionallycombined with an Ethocel (trade mark) polymer. Such polymers maysuitably be used in combination with a plasticiser such as hydrogenatedcastor oil. The barrier layer may also include conventional binders,fillers, lubricants and compression acids etc such as Polyvidon K30(trade mark), magnesium stearate, and silicon dioxide, e.g. Syloid 244(trade mark).

[0109] The tablet formulation of the invention may be wholly or partlycovered by a coating layer, which may be a protective layer to preventingress of moisture or damage to the tablet. The coating layer mayitself contain active material content, and may, for example, be animmediate release layer, which immediately disintegrates in contact withwater or aqueous media to release its active material content, forexample amoxycillin and potassium clavulanate. Preferred coatingmaterials comprise hydroxypropylmethylcellulose and polyethylene glycol,with titanium dioxide as an opacifying agent, for instance as describedin WO 95/28927 (SmithKline Beecham).

[0110] As well as active material content etc, the tablet of theinvention may also include a pH modifying agent, such as a pH buffer,which may be contained in either the immediate-, or slow-release layers,or in a coating around all or part of the tablet. A suitable buffer iscalcium hydrogen phosphate.

[0111] In a tablet without a barrier layer, the immediate release layercomprises from 50 to 60% and the slow release layer comprises from 40 to50% of the overall tablet weight. When a barrier layer is present, theimmediate release layer typically comprises from 40 to 50%, the slowrelease layer comprises from 35 to 45%, and the barrier layer comprisesfrom 5 to 20% of the overall tablet weight.

[0112] It is found that a satisfactory pharmacokinetic profile may beobtained from a bilayered tablet of the present invention without theneed to include a barrier layer. Accordingly, a bi-layer tablet ispreferred. This also reduces the complexity of the manufacturingprocess.

[0113] It will be appreciated that 1000, 875 and 750/62.5 mg layeredtablets having an immediate release layer and a slow release layer arenovel. Accordingly, in a further aspect, the present invention providesfor a pharmaceutical layered tablet formulation comprising an immediaterelease layer and a slow release layer and comprising from 700 to 1250mg amoxycillin and a pro rata amount of potassium clavulanate,preferably 1000, 875 or 750 mg ±5% amoxycillin and 62.5 mg ±5% potassiumclavulanate, in a nominal ratio of about 16:1, 14:1 or 12:1,respectively, in combination with pharmaceutically acceptable excipientsor carriers. Preferably, the layered tablet is a bi-layered tablet.

[0114] Suitably the tablet formulations of the invention may be formedby known compression tabletting techniques, for example using a knownmulti-layer tabletting press. Preferably, in a preliminary step,slugging or roller compaction is used to form granulates. Lubricants andcompression aids (if used) are then added, to form a compression blendfor subsequent compaction.

[0115] Preferred bilayer tablets of the present invention may be made bya process which comprises, as an early phase, the formation of slowrelease compacted granules, comprising the steps of milling sodiumamoxycillin, a portion of the diluent/compression aid such asmicrocrystalline cellulose (typically about 30%), a portion of thelubricant (typically about 70%) and a pharmaceutically acceptableorganic acid such as a fruit acid, for instance citric acid, and thenblending with a release retarding polymer such as xanthan gum, ifpresent, and a compression aid such as colloidal silicon dioxide,compacting the blend, for instance in a roller compactor or by slugging,and then milling, to form slow release granules. Preferably suchgranules have a size in the range 100 to 1000 microns. The incorporationof xanthan gum appears to also have an unexpected benefit onprocessibility.

[0116] Such slow release compacted granules may then be blended withother excipients such as the remaining magnesium stearate andmicrocrystalline cellulose, to form a slow release compression blend.

[0117] In addition, amoxycillin trihydrate, potassium clavulanate(preferably as as 1:1 blend with microcrystalline cellulose),microcrystalline cellulose (a portion of total used), are milled andblended with a lubricant such as magnesium stearate (preferably about50% f total), and then compacted, for instance in a roller compactor orby slugging, and milled to form immediate release compacted granules.These immediate release compacted granules may then be blended withother excipients such as the remaining magnesium stearate andmicrocrystalline cellulose (about 13%), a compression aid such ascolloidal silica, and a disintegrant such as sodium starch glycollate,to form an immediate release compression blend.

[0118] The immediate release and slow release compression blends maythen be compressed as separate layers on a bilayer tablet press, to formbilayer tablets.

[0119] Such slow release granules are novel. Accordingly, in a furtheraspect, the present invention provides for compacted granules comprisinga soluble salt of amoxycillin, for instance sodium amoxycillin, adiluent/compression aid, and an organic acid or a release retardingpolymer or a mixture thereof, as hereinbefore defined. In a yet furtheraspect, the present invention also provides for compacted granulescomprising amoxycillin trihydrate, a diluent/compression aid, and arelease retarding polymer, as hereinbefore defined Alternatively, a drydensification process may be used, e.g. briquetting. Typically theactive material content, pH modifiers, buffers, fillers and/or diluent,release retarding agents, disintegrants and binders, when used aremixed, then lubricants and compression aids are added. The completemixture may then be compressed under high pressure in the tablet press.A wet granulation process may be also be used, for instance withisopropanol as the solvent and Polyvidon K-30 (trade mark) as the wetgranulating aid.

[0120] A barrier layer, if present, may typically be made up by a wetgranulation technique, or by dry granulation techniques such as rollercompaction. Typically the barrier material, e.g. Methocel (trade mark)is suspended in a solvent such as ethanol containing a granulation acidsuch as Ethocel or Polyvidon K-30 (trade mark), followed by mixing,sieving and granulation. Typically a first layer may be formed, then abarrier layer deposited upon it, e.g. by compression, spraying orimmersion techniques, then the second layer may be formed so that thebarrier layer is sandwiched between the first and second layers.Additionally, or alternatively, the first and second layers may beformed and a barrier layer may then be formed, for instance bycompression, spraying or immersion, on one or more of the end faces ofthe tablet.

[0121] A process for the preparation of crystallised sodium amoxycillinis described in EP-A-0 131 147 (Beecham Group plc).

[0122] Potassium clavulanate is known to be extremely water sensitive.Therefore tablet formulations which contain potassium clavulanate shouldbe made up in dry conditions, preferably at 30% relative humidity orless, and the ingredients of the formulation should be pre-dried whereappropriate. Tablet formulations of the invention should be stored incontainers which are sealed against the ingress of atmospheric moisture.

[0123] Tablet cores may then be coated with a coating layer which may beapplied form an aqueous or an organic solvent system, preferably anaqueous solvent system, to provide film coated tablets.

[0124] The invention also provides a method for the manufacture of atablet formulation as described above comprising the steps of formingsaid first and second layers, and any barrier layers and coatinglayer(s) which may be present.

[0125] In addition to the layered tablet approach hereinbeforedescribed, other types of tablet may be used to provide an immediaterelease phase and a slow release phase, using the excipientshereinbefore described but providing the phases in different formats.Thus, the slow release phase may form the core of a tablet which is thensurrounded by an outer casing forming the immediate release phase,optionally with an intermediate coating layer around the core and/or afinal coating layer around the outer casing (see WO 95/28148, SmithKlineBeecham). The slow release phase may also be provided as granules whichare dispersed in a matrix of amoxycillin and potassium clavulanate, thematrix forming the immediate release phase (see WO 96/04908, SmithKlineBeecham).

[0126] In a further variant, a monolith modified release tablet may beprepared from slow release compacted granules comprising amoxycillin, adiluent/compression aid such as microcrystalline cellulose, and apharmaceutically acceptable organic acid such as a fruit acid, forinstance citric acid (if amoxycillin is present as a soluble saltthereof), or a release retarding polymer such as xanthan gum or amixture thereof, preferably a release retarding polymer (as hereinbeforedescribed); and immediate release compacted granules comprisingamoxycillin and potassium clavulanate (as hereinbefore described) orimmediate release compacted granules comprising amoxycillin andpotassium clavulanate, for instance in a 2:1 ratio, and furtherimmediate release compacted granules comprising amoxycillin (asdescribed in WO 98/35672, SmithKline Beecham LaboratoiresPharmaceutiques), the granules being combined with extragranularexcipients to form tablets. Such granules may also be processed intoother pharmaceutical formulations, for instance single dosage sachets,capsules or chewable tablets comprising a unit dosage as hereinbeforedescribed.

[0127] Chewable tablets according to the present invention typicallycomprise a chewable base formed from, for instance, mannitol, sorbitol,dextrose, fructose or lactose alone or in combination. A chewable tabletmay also comprise further excipients, for instance, disintegrants,lubricants, sweetening agents, colouring and flavouring agents. Suchfurther excipients together will preferably comprise from 3 to 10%, morepreferably 4 to 8%, yet more preferably 4 to 7% by weight of the tablet.Disintegrants may be present in from 1 to 4%, preferably from 1 to 3%,more preferably from 1 to 2% by weight of the tablet. Representativedisintegrants include crospovidone, sodium starch glycollate, starchessuch as maize starch and rice strach, croscarmellose sodium andcellulose products such as microcrystalline cellulose, microfinecellulose, low substituted hydroxy propyl cellulose, either used singlyor in admixture. Preferably, the disintegrant is crospovidone.Lubricants may be present in from 0.25 to 2.0%, preferably from 0.5 to1.2% by weight of the tablet. Preferred lubricants include magnesiumstearate. Preferably, the sweetening agent is an artificial sweeteningagent such as sodium saccharin or aspartame, preferably aspartame, whichmay be present in from 0.5 to 1.5% by weight of the tablet. Preferably,a tablet of the present invention is substantially free of sugar(sucrose). Preferred flavouring agents include fruit flavours which maybe natural or synthetic, for instance peppermint, cherry and banana, ora mixture thereof.

[0128] Single dose sachets according to the present invention comprise,in addition to the drug substance, excipients typically included in asachet formulation, such as a sweetener, for instance aspartame,flavourings, for instance fruit flavours, optionally a suspending agentsuch as xanthan gum, as well as silica gel, to act as a desiccant.

[0129] Capsules according to the present invention comprise, in additionto the drug substance, excipients typically included in a capsule, forinstance starch, lactose, microcrystalline cellulose, magnesiumstearate. It will be appreciated that due to the hygroscopic nature ofclavulanate, the use of materials such as gelatin for forming thecapsules should be avoided. Preferably, capsules are prepared frommaterials such as HPMC or a gelatin/PEG combination.

[0130] In a further embodiment, the slow release phase may be providedas a separate component, for instance as a separate tablet, so that theunit dosage is provided as a combination of a conventional component inwhich amoxycillin and potassium clavulanate are released immediately,optionally with a conventional amoxycillin formulation such as a tablet,and a further formulation, for instance a tablet, comprising amoxycillin(and no potassium clavulanate) from which amoxycillin is releasedslowly. The weight of potassium clavulanate and the combined weights ofamoxycillin in the conventional and slow release formulations willprovide the overall unit dosage. Thus, for instance a dosage of 2000/125mg may be provided by a combination of an existing 500/125 mgamoxycillin/potassium clavulanate tablet and a 500 mg amoxycillin tabletin combination with a slow release tablet comprising 1000 mg ofamoxycillin. Furthermore, a dosage of 1750/125 mg may be provided by anexisting 875/125 mg tablet (as described in WO 95/28927, SmithKlineBeecham) in combination with a slow release tablet comprising 875 mg ofamoxycillin. In addition, a dosage of 1500/125 mg may be provided by anexisting 500/125 mg tablet and an existing 500 mg tablet of amoxycillinin combination with a slow release tablet comprising 500 mg ofamoxycillin. Accordingly, in a further aspect, the present inventionprovides for a kit comprising a conventional (immediate release) tabletcomprising amoxycillin and potassium clavulanate, optionally with aconventional (immediate release) tablet comprising amoxycillin, and aslow release tablet comprising amoxycillin (and no potassiumclavulanate).

[0131] In a further aspect, the present invention provides for apharmaceutical formulation, preferably a tablet, comprising amoxycillin(as the sole active ingredient) formulated with a release retardingexcipient which causes a slow release of the amoxycillin from theformulation, and excluding; tablets which comprise 750 mg or less ofamoxycillin in which the amoxycillin is present essentially asamoxycillin trihydrate; or tablets comprising from 400 to 500 mgamoxycillin in which amoxycillin is present as a mixture comprising atleast 70% amoxycillin trihydrate and up to 30% sodium amoxycillin incombination with hydroxypropyl methylcellulose as a release retardingexcipient.

[0132] Such formulations may comprise from 100 to 1250 mg amoxycillinwhich may be amoxycillin trihydrate or (crystallised) sodium amoxycillinor a mixture thereof, for instance 500, 875 or 1000 mg amoxycillin.Suitable excipients for slow release are those hereinbefore describedfor slow release layers. The formulation may comprise from 1 to 25%,preferably from 2 to 15%, more preferably 4 to 10% of xanthan gum, orfrom 10 to 25, preferably 15 to 20% of a hydroxypropyl-methylcellulose,for instance Methocel K100LV or Methocel K4M. Alternatively, suchformulations may comprise citric acid, optionally with xanthan gum, ashereinbefore described.

[0133] Preferably, the unit dosage forms of the present invention arepackaged in containers that inhibit the ingress of atmospheric moisture,for instance blister packs, tightly closed bottles or desiccated pouchpacks etc which are conventional in the art. Preferably, bottles alsoinclude a desiccating material, to preserve the clavulanate. Preferredbottles include HDPE bottles. Preferred blister packs includecold-formed blister packs in which each blister may contain one tablet,or two tablets,where the unit dosage is two tablets, for instance2×1000/62.5 mg tablets, to improve patient compliance.

[0134] The invention will now be described by way of example only withreference to the accompanying drawings, in which:

[0135]FIG. 1 shows the structure of various types of layered tablets ofthe present invention, in particular the structure of substantiallycylindrical compressed tablets are shown in longitudinal section. InFIG. 1A, the tablet comprises a first layer (1) and a second layer (2),without any barrier layer or coating layer. In FIG. 1B, the tabletcomprises a first layer (1), a second layer (2), and a barrier layer (3)sandwiched between the first and second layers (1) and (2). In FIG. 1C,the tablet comprises a first layer (1), a second layer (2), and abarrier layer (3) located on the end face of the second layer (2). InFIG. 1D, the tablet comprises a first layer (1), a second layer (2), abarrier layer (3) sandwiched between the first and second layers (1) and(2), and a coating layer (4) which partly covers the tablet. The dottedline shows the possibility of the coating layer (4A) covering the entiretablet. In FIG. 1E, the tablet comprises a first layer (1) a secondlayer (2), and a third layer (3) intermediate between the first andsecond layers (1) and (2). All three of these layers (1), (2) and (3)include active material content.

[0136] All publications and references, including but not limited topatents and patent applications, cited in this specification are hereinincorporated by reference in their entirety as if each individualpublication or reference were specifically and individually indicated tobe incorporated by reference herein as being fully set forth. Any patentapplication to which this application claims priority is alsoincorporated by reference herein in its entirety in the manner describedabove for publications and references.

[0137] The foregoing examples describe tablet formulations whichcomprise potassium clavulanate. This is known to be extremely watersensitive. Therefore such tablet formulations should be made up in dryconditions, preferably at 30% relative humidity or less, and theingredients of the formulation should be pre-dried where appropriate.

EXAMPLE 1 1000/62.5 mg Modified Release Tablet

[0138] Ingredient mg/tablet

% w/w

Immediate Release Layer Amoxycillin Trihydrate 654.1* 40.88 (ERR < 40%)Potassium Clavulanate 76.2# 4.76 Microcrystalline Cellulose 136.4 8.52Sodium Starch Glycollate 18.0 1.12 Colloidal Silicon Dioxide 6.3 0.39Magnesium Stearate 9.0 0.56 Total (Immediate Release Layer) 900.0 56.23Slow Release Layer Crystallised Sodium Amoxycillin 480.8** 30.05Microcrystalline Cellulose 113.2 7.08 Xanthan Gum 14.0 0.87 Citric Acid78.0 4.87 Colloidal Silicon Dioxide 1.50 0.08 Magnesium Stearate 14.00.87 Total (Sustained Release Layer) 700.0 43.74 Film coat OpadryYS-1-7700 - Composition: Hydroxypropylmethylcellulose 2910 6cp 11.6Hydroxypropylmethylcellulose 2910 15cp 3.9 Titanium dioxide 15.1Polyethylene Glycol 3350 2.3 Polyethylene Glycol 8000 2.3 Total weightof coated tablet 1635.2

EXAMPLE 2 1000/62.5 mg Modified Release Tablet

[0139] The immediate release layer and film coat are as for the tabletof Example 1 Ingredient mg/tablet

% w/w

Slow Release Layer Crystallised Sodium Amoxycillin 480.8** 30.05Microcrystalline Cellulose 127.2 7.95 Citric Acid 78.0 4.87 ColloidalSilicon Dioxide 1.5 0.09 Magnesium Stearate 14.0 0.87 Total (SlowRelease Layer) 700.0 43.74 Total Weight of coated tablet 1635.2

[0140] Preparation of Modified Release Tablets

[0141] Modified release tablets were prepared according to the processflow diagram shown in FIG. 2. In brief, immediate and modified releaseblends are prepared which involve initial sieving and milling, asindicated, before roller compaction in a Chilsonater and furthermilling, sieving and blending. The two containers comprising amoxycillintrihydrate and the two containers comprising sodium amoxycillin compriseabout equal weights of amoxycillin trihydrate and sodium amoxycillin,respectively.

[0142] For the IR blend, the Chilsonator settings were: roll size,width=4 inches, diam=10 inches; hydraulic pressure=900-1100 psi, airpressure=25-35 psi, roll speed=15-25 rpm, horizontal auger speed=15-30rpm, vertical auger speed=300-350 rpm.

[0143] For the SR blend, the Chilsonator settings were: roll size,width=4 inches, diam=10 inches; hydraulic pressure=500-700 psi, airpressure=15-20 psi, roll speed=15-25 rpm, horizontal auger speed=30-35rpm, vertical auger speed=300-350 rpm.

[0144] The two blends were then compressed as separate layers in abilayer tablet press equipped with punches measuring 0.0406 inches by0.8730 inches and having a modified capsule shape. For the first(immediate release)layer, there was no pre-compression, and a maincompression of less than 10 KN. For the second layer, there was apre-compression of less than 20 KN, and a main compression of less than60 KN. The tablets thus produced had a total weight of 1600 mg ±48 mg, ahardness in the range 8 to 18 SCU and a friability of less than 0.5%.

[0145] Finally, the tablet cores were coated with an aqueous filmcoating, using a 15% solids aqueous suspension, in a 60 inch coating panwhich could accommodate up to 300 kg charge of tablets. The pan wasequipped with 4 spray guns and rotated at 3 to 5 rpm. The inlet air wasdehumidified with the temperature in the range 56 to 60° C. whilst theexhaust air humidity was in the range 4 to 12% and the temperature inthe range 43 to 50° C. The spray rate was 80 to 120 ml/min/spray gun.

EXAMPLE 3 Slow Release Tablet (875 mg)

[0146] mg/ta

(a) Sodium Amoxycillin Tablet Crystallised Sodium Amoxycillin 91%* 96

7

Dried Microcrystalline Cellulose 27

2

Magnesium Stearate

Xanthan gum 200 mesh** 1 Total 1 (b) Sodium Amoxycillin Tablet withcitric acid Crystallised Sodium Amoxycillin 91%* 96

6

Dried Microcrystalline Cellulose 28

1

Magnesium Stearate 1

Citric acid 1

Xanthan gum 200 mesh**

Total 1 (c) Amoxycillin Trihydrate Tablet Amoxycillin Trihydrate 86%* 10

7

Dried Microcrystalline Cellulose 2

1

Magnesium Stearate

Xanthan Gum, 200 mesh**

Total 1

EXAMPLE 4 875/62.5 mg Modified Release Tablet

[0147] Slow Release Layer

[0148] This may be formed using half the quantities given above, for aslow release layer comprising about 438 mg amoxycillin. Immediaterelease layer - 1 Amoxycillin trihydrate 507 mg (equiv to amoxycillinfree acid) (438) Potassium clavulanate 71.8 (equivalent to clavulanicacid) (62.5) Microcrystalline cellulose (Avicel PH102) 125 Sodium starchglycollate (Explotab) 26 Magnesium stearate 6.5

[0149] The immediate release layer comprises nominally 438/62.5 mgamoxycillin/clavulanate. Immediate release layer - 2 Amoxycillintrihydrate 507 mg (equiv to amoxycillin free acid) (438) Potassiumclavulanate 71.8 (equivalent to clavulanic acid) (62.5) Microcrystallinecellulose (Avicel PH102) 135 Sodium starch glycollate (Explotab) 34 Talc67 Magnesium stearate 25 Silica (Syloid) 17

[0150] The immediate release layer comprises nominally 438/62.5 mgamoxycillin/clavulanate.

[0151] Barrier Layers

[0152] Barrier layers and methods for their preparation are described inWO 95/20946 (SmithKline Beecham) whose disclosure is incorporated hereinby reference in its entirety.

[0153] Preparation of Tablets

[0154] The active ingredients, fillers and diluents (microcrystallinecellulose), release controlling agents (if present), disintegrants(crospovidone, sodium starch glycollate) etc are mixed. Lubricants(talc, Mg-stearate) and colloidal silicon dioxide (Syloid 244) areadded, and mixing is continued for another minute. The complete mixtureis slugged on a tablet press or roller compacted (briquetting step),followed by size reduction (Apex, Fitzmill, Frewitt) and passage throughan oscillatory sieve or particle size classifier (Kason, Sweco). If theflow properties are unsatisfactory, the briquetting step is repeated.Separate compressed blends are prepared for the immediate and slowrelease layers, and barrier layer, if present.

[0155] In some cases, where the bulk density is rather low, a densifyingstep (pre-tabletting and sieving as in the briquetting method) may berequired in order to achieve the nominal weight of a particular layer.

[0156] The blends are then compressed as separate layers on a layertablet press to form bilayered tablets. Tablets may then be coated witha white opaque coating, for instance the product Opadry, Opaspray(Colorcon).

EXAMPLE 5 Dissolution Testing Methods

[0157] The release of amoxycillin and clavulanate from tablets intostatic media was measured using the <711> Dissolution Test, Apparatus 2,provided in USP 23, 1995. Test specifications: Temperature: 37.0 ± 0.5°C. Medium: Deionized water, 900 mL Paddle speed 75 rpm

[0158] Method

[0159] Aliquots of medium were removed for assay after 15, 30, 45, 60,90, 120, 150, 180, 240, 300 360, 420 and 480 min, each aliquot beingreplaced simultaneously by an equal volume of medium to maintainconstant volume. The amount of drug substance was determined by UVspectrometry, at 272 nM. The resulting dissolution profile for thetablets of Example 1 and 2 are shown as FIG. 3.

[0160] in vivo Pharmacokinetic Evaluation of Formulations

[0161] The bioavailability of dosages according to the present inventionwere evaluated in two human volunteer studies, Study A and Study B.These were open, randomised, crossover studies in healthy volunteers.Each dosage was administered with the aid of approximately 200 mL water,at the start of a light breakfast and after an overnight fast. Bloodsamples were collected into tubes containing EDTA at nominal times ofpre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after startof dosing, for assay of plasma levels of amoxycillin and clavulanate.Samples were cooled in an ice-bath awaiting further processing. Plasmawas separated by refrigerated centrifugation at 4° C. and transferred toappropriately labelled polypropylene specimen containers and storedfrozen at approximately −70° C. until assayed.

[0162] Samples were assayed for amoxycillin using a method based onprotein precipitation with acetonitrile. Amoxycillin was extracted fromhuman plasma (50 μL) by means of protein precipitation, usingacetonitrile containing the internal standard and quantified byLC/MS/MS. Specifically, human plasma (50 μL) was pipetted into a 1.5 mLEppendorf tube followed by the addition of acetonitrile containing theinternal standard ([¹³C₆]-amoxycillin, 200 μL). The tube was capped,vortex mixed and shaken for approximately 15 minutes. After centrifugingthe sample (approximately 11,000×g, for 15 minutes), the supernatant wastransferred to a silanised 1.1 mL tapered autosampler vial containing200 μL of 5 mM ammonium acetate solution. An aliquot of extract wasinjected onto the BPLC/MS/MS system for analysis. The mass spectrometerwas operated in positive ion mode, employing a Turbo IonSpray interface.Multiple reaction monitoring (MRM) was used to detect the components,amoxycillin and [¹³C₆]-amoxycillin. The MRM procedure involves (1) massselection of a characteristic ion of the required drug or internalstandard in the first quadrupole mass analyser (2) fragmentation of theselected ion in the instrument's collision cell (3) detection of afragment ion which is characteristic of the compound of interest.Quantification is performed by comparison of the chromatographic peakareas of the drug relative to the area of the internal standard. Linearresponses in the analyte/internal standard peak area ratios wereobserved for analyte concentrations ranging from 0.05 μg/mL (lower limitof quantification; LLQ) to 10 μg/mL (upper limit of quantitication:ULQ).

[0163] Samples were assayed for clavulanate using a method based onprotein precipitation with acetonitrile. Clavulanate was extracted fromhuman plasma by means of liquid/liquid using internal standard andquantified by LC/MS/MS. Specifically, human plasma (50 μL) was pipettedinto a 1.5 mL Eppendorf tube followed by 0.2 mM ammonium acetate (200μL) before addition of acetonitrile containing the internal standard(6-aminopenicillanic acid, 400 μL). The tube was capped, vortex mixedand shaken for approximately 20 minutes. After centrifuging the sample(approximately 14,500×g, for 15 minutes), the supernatant wastransferred to a clean eppendorf tube and dichloromethane added. Afterfurther mixing and centrifugation (approximately 14, 500×g for 10minutes) supernatent (no more than 150 μL) was transferred to a tapered1.1 mL autosampler vial and left uncapped for at least 20 minutes toallow any traces of dichloromethane to evaporate. An aliquot of theextract was injected onto the HPLC/MS/MS system for analysis. The massspectrometer was operated in positive ion mode, employing a TurboIonSpray interface. Multiple reaction monitoring (MRM) was used todetect the components, clavulanate and 6-aminopenicillanic acid. The MRMprocedure involves (1) mass selection of a characteristic ion of therequired drug or internal standard in the first quadrupole mass analyser(2) fragmentation of the selected ion in the instrument's collision cell(3) detection of a fragment ion which is characteristic of the compoundof interest. Quantification is performed by comparison of thechromatographic peak areas of the drug relative to the area of theinternal standard. Linear responses in the analyte/internal standardpeak area ratios were observed for analyte concentrations ranging from0.05 μg/mL (lower limit of quantification; LLQ) to 10 μg/mL (upper limitof quantification: ULQ).

[0164] QC samples were assayed with each batch of samples againstseparately prepared calibration standards. The results of the QC sampleswere used to assess the day-to-day performance of the assay.

[0165] Plasma concentration-time data for each subject in each regimenwere analysed by non-compartmental methods using the non-compartmentalpharmacokinetic analysis program WinNonlin Professional Version 1.5. Allcalculations were based on actual sampling times. Pharmacokineticparameters determined included maximum observed plasma concentration(Cmax) and time to reach maximum plasma concentration (Tmax). Theapparent terminal elimination rate constant (lz) was derived from thelog-linear disposition phase of the concentration-time curve usinglinear least-squares regression with visual inspection of the data todetermine the appropriate number of points to calculate lz. The apparentterminal elimination half-life (T1/2) was calculated as ln(2)/lz.

[0166] Area under the plasma concentration-time curve from time zero tothe last quantifiable plasma concentration [AUC(0-t)] was determinedusing the linear trapezoidal rule for each incremental trapezoid and thelog trapezoidal rule for each decremental trapezoid [Chiou W L., J.Pharmacokinet. Biopharm., 1978, 6, 539-547]. The area under the plasmaconcentration-time curve extrapolated to infinity [AUC(0-inf)] wascalculated as the sum of AUC(0-t) and C(t)/lz, where C(t) was thepredicted concentration from the log-linear regression analysis at thelast measurable time point.

[0167] The time above the minimum inhibitory plasma concentration(T>MIC) was calculated manually by graphical interpolation, where theminimum inhibitory plasma concentrations was defined as 4 ug/mL foramoxycillin.

[0168] The mean concentration-time profiles for amoxycillin and forclavulanate were derived at each nominal sampling time for eachformulation. In cases where a post-dose value was not quantifiable, avalue of ½ the LLQ (0.050 ug/mL) was assigned to determine the meanvalue. Where the calculated mean value was less than the LLQ or wasbased on greater than 50% NQ values, a value of NQ was assigned for thatsampling time.

[0169] Log_(e)-transformed Cmax and untransformed T>NHC for each of theformulations were analysed using Analysis of Covariance (ANCOVA) fittinga single term for formulation and fitting the data from the referenceformulation as a co-variate. The 95% confidence intervals for the meansof each formulation were constructed using the residual variance fromthe model. For Cmax, the confidence interval estimates on the log scalewere then back-transformed to obtain the 95% confidence intervals of thegeometric mean. These results were displayed graphically.

[0170] Assumptions underlying the analyses were assessed by inspectionof residual plots. Homogeneity of variance was assessed by plotting thestudentised residuals against the predicted values from the model, whilenormality was assessed using normal probability plots. Particularattention was paid to any outlying values observed with the referenceformulation.

[0171] Study A

[0172] The first study compared three modified release dosages of1750/125 mg (formulations I to III) and a fourth modified releasedosages of 1500/125 mg (formulation IV) against an immediate releasedosage of 1750/125 mg (formulation V), as follows:

[0173] (a) a dosage of 1750/125 mg amoxycillin/potassium clavulanate,made up of a combination of one modified release tablet comprising875/125 mg amoxycillin trihydrate/clavulanate and 4% xanthan gum and oneimmediate release tablet comprising 875 mg amoxycillin trihydrate(formulation I);

[0174] (b) a dosage of 1750/125 mg amoxycillin/potassium clavulanate,made up of a combination of one modified release tablet comprising875/125 mg crystallised sodium amoxycillin/clavulanate and 4% xanthangum and one immediate release tablet comprising 875 mg amoxycillintrihydrate (formulation II);

[0175] (c) a dosage of 1750/125 mg amoxycillin/potassium clavulanate,made up of a combination of one modified release tablet comprising875/125 mg crystallised sodium amoxycillin/clavulanate, citric acid (156mg) and 2% xanthan gum and one immediate release tablet comprising 875mg amoxycillin trihydrate (formulation III);

[0176] (d) a dosage of 1500/125 mg amoxycillin/potassium clavulanate(made up of a modified release tablet comprising 500/125 mg crystallisedsodium amoxycillin/potassium clavulanate and two immediate releasetablet comprising 500 mg amoxycillin trihydrate (Amoxyl, SmithKlineBeecham) (formulation IV); and

[0177] (e) a dosage of 1750/125 mg amoxycillin/potassium clavulanate,made up of a combination of one immediate release tablet comprising875/125 mg amoxycillin trihydrate/clavulanate (Augmentin, SmithKlineBeecham) and one immediate release tablet comprising 875 mg amoxycillintrihydrate (Amoxyl, SmithKline Beecham) (formulation V).

[0178] Results Formulatio

n Cmax¹ T > MIC

1,2

AUC

1,3

I 8 12.75 (4.96

4.5 (1.8) 47.83 II 8 18.56 (4.72

4.4 (1.0) 57.46 III 8 13.03 (2.34

5.73 (2.54) 54.93 IV 8 17.33 (4.66

4.8 (0.9) 56.71 V 40 20.21 (6.09

4.2 (0.9) 56.33

[0179] The pharnacokinetic profile is shown in FIG. 4.

[0180] Study B

[0181] The second study investigated two different modified releasedosages of 2000/125 mg (formulations VI and VII) against an immediaterelease dosage of 2000/125 mg (formulation VIII), as follows:

[0182] (a) a dosage of 2000/125 mg amoxycillin/potassium clavulanate,made up of two bilayer tablets according to Example 1 (formulation VI);

[0183] (b) a dosage of 2000/125 mg amoxycillin/potassium clavulanate,made up of two bilayer tablets according to Example 2 (formulation VII);

[0184] (c) a dosage of 2000/125 mg amoxycillin/potassium clavulanate,made up of a combination of three tablets each comprising 500 mgamoxycillin (Amoxyl, SmithKline Beecham) and one tablet comprising 500mg amoxycillin and 125 mg potassium clavulanate (Augmentin, SmithKlineBeecham) (formulation VIII).

[0185] Results Formulation N Cmax¹ T > MIC

1,2

T > MIC

1,3

AUC

1,4

VI 7 17.41 (1.93

6.0 (1.3) 4.8 (1.2) 74.9 VII 8 17.46 (6.02

5.9 (1.3) 4.0 (1.3) 71.5 VIII 12 23.75 (5.73

4.9 (1.1) 3.5 (1.0) 69.2

[0186] Comparison of the AUC values for formulations VI and VII (bilayertablets) against VIII (immediate release tablets) shows that theabsorption of the amoxycillin component has not been compromised byformulating a part of it in a slow release layer. This means that thereis no extra, unabsorbed amoxycillin which may otherwise cause problemsfurther down in the GI tract, for instance due to a lack of absorptionand destruction of symbiotic bacteria

[0187] It was also found that for formulation VI, there was lessinter-subject variability in the amoxycillin plasma concentrations thanfor formulation VII. These formulations were the same, except thatformulation VI also comprised xanthan gum (2%) in the slow releaselayer.

[0188] The pharmacokinetic profile for amoxycillin plasma concentrationis shown in FIG. 5 (in which A is formulation VI, B is formulation VII,D is formulation VIII).

[0189] The pharmacokinetic profile for the clavulanate component wassubstantially the same for the bilayer tablets and the immediate releasetablets, showing that the bioavailability thereof was not compromised byincorporation into the immediate release layer of a bilayer tablet.

[0190] The present invention also extends to formulations which arebioequivalent to the tablets of formulations VI and VII, in terms ofboth rate and extent of absorption, for instance as defined by the USFood and Drug Administration and discussed in the so-called “OrangeBook” (Approved Drug Products with Therapeutic Equivalence Evaluations,US Dept of Health and Human Services, 19th edn, 1999).

[0191] Reference Data

[0192] The existing Augmentin 875/125 mg tablet has a C_(max) value of11.6±2.8 μg/ml (Physicians Desk Reference, Medical Economics Co, 52edition, 1998, 2802). The time above MIC was about 40% of the 12 hourdosing interval for an MIC of 2 μg/ml and about 30% for an MIC of 4μg/ml (SmithKline Beecham data).

What is claimed is:
 1. A method of treating a bacterial infection in ahuman in need thereof, which method comprises administering to saidhuman a dosage of a therapeutically effective amount of amoxycillin andpotassium clavulanate, such that the amount of amoxycillin is in therange of 1900 to 2600 mg and the amount of potassium clavulanate is suchthat the weight ratio of amoxycillin to potassium clavulanate is fromabout 2:1 to 20:1, at a dosage regimen interval of about 12 hours. 2.The method according to claim 1 in which the weight ratio of amoxycillinto potassium clavulanate is from about 14:1 to 20:1.
 3. The methodaccording to claim 1 in which the dosage regimen provides a mean plasmaconcentration of amoxycillin of 4 μg/mL for at least 4.4 hours and amean maximum plasma concentration (C_(max)) of amoxycillin of at least12 μg/mL.
 4. The method according to claim 3 in which the dosage regimenprovides a mean plasma concentration of amoxycillin of 4 μg/mL for atleast 4.8 hours and a mean maximum plasma concentration (C_(max)) ofamoxycillin of at least 16 μg/mL.
 5. The method according to claim 1 inwhich the dosage regimen provides a mean plasma concentration ofamoxycillin of 8 μg/mL for at least 4.4 hours.
 6. The method accordingto claim 1 in which the dosage is delivered from an immediate releaseformulation.
 7. The method according to claim 6 in which the dosage isprovided as a single tablet, or as a number of smaller tablets, some ofwhich may be the same and some of which may comprise amoxycillin onlyand no potassium clavulanate.
 8. The method according to claim 7 inwhich the dosage is 2000/125, 2250/125 or 2500/125 mg of amoxycillin andpotassium clavulanate, respectively.
 9. The method according to claim 1in which the dosage is delivered from a modified release formulation.10. The method according to claim 9 in which the dosage is provided as anumber of tablets, some of which may be the same and some of which maycomprise amoxycillin only and no potassium clavulanate.
 11. The methodaccording to claim 9 in which the dosage is 2000/125, 2250/125 or2500/125 mg of amoxycillin and potassium clavulanate.
 12. The methodaccording to claim 1 in which the infection is caused by the organism S.pneumoniae (including Drug Resistant and Penicillin Resistant Spneumoniae), H. influenzae or M. catarrhalis.
 13. A method of treating abacterial infection in a human in need thereof, which method comprisesadministering to said human a dosage of a therapeutically effectiveamount of amoxycillin and potassium clavulanate such that the amount ofamoxycillin is in the range 1400 to 1900 mg, and an amount of potassiumclavulanate such that the weight ratio of amoxycillin to potassiumclavulanate is from 2:1 to 14:1, at a dosage regimen interval of about12 hours, such that the regimen provides a mean plasma concentration ofamoxycillin of 4 μg/mL for at least 4.4 h, and a mean maximum plasmaconcentration (Cmax) of amoxycillin of at least 12 μg/mL.
 14. The methodaccording to in claim 13 in which the weight ratio of amoxycillin topotassium clavulanate is from 12:1 to 14:1.
 15. The method according toclaim 13 in which the dosage regimen provides a mean plasmaconcentration of amoxycillin of 4 μg/ml for at least 4.8 hours and amean maximum plasma concentration (Cmax) of amoxycillin of at least 16μg/ml.
 16. The method according to claim 13 in which the dosage isdelivered from a modified release formulation.
 17. The method accordingto claim 13 in which the dosage is 1500/125 or 1750/125 mg ofamoxycillin and potassium clavulanate.
 18. The method according to claim13 in which the infection is caused by the organism S. pneumoniae(including Drug Resistant and Penicillin Resistant S pneumoniae), H.influenzae or M. catarrhalis.
 19. An immediate release pharmaceuticalformulation comprising from 950 to 1300 or 1900 to 2600 mg ofamoxycillin and an amount of potassium clavulanate such that the weightratio of amoxycillin to potassium clavulanate is from 14:1 to 20:1, incombination with a pharmaceutically acceptable carrier or excipient. 20.The immediate release pharmaceutical tablet formulation according toclaim 19 comprising 1000 mg ±5% amoxycillin and 62.5 mg ±5% potassiumclavulanate, in a nominal ratio of about 16:1, in combination with apharmaceutically acceptable carrier or excipient.
 21. The immediaterelease pharmaceutical formulation according to claim 19 in the form ofa single dose sachet comprising 2000, 2250 or 2500 mg ±5% amoxycillinand 125 mg ±5% potassium clavulanate, in a nominal ratio of about 16:1,18:1 or 20:1, respectively, or the corresponding half quantitiesthereof, in combination with a pharmaceutically acceptable carrier orexcipient.
 22. The immediate release formulation according to claim 19in the form of a dispersible tablet, chewable tablet, effervescentdispersible or effervescent chewable tablet comprising 2000, 2250, or2500 mg amoxycillin and 125 mg ±5% potassium clavulanate, in a nominalratio of about 16:1, 18:1 or 20:1, respectively, or the correspondinghalf quantities thereof, in combination with a dispersible, or chewablebase and, if effervescent, an effervescent coupling agent, and apharmaceutically acceptable or carrier or excipient.
 23. A modifiedrelease pharmaceutical formulation comprising amoxycillin and potassiumclavulanate in a (w/w) ratio from about 2:1 to 20:1, comprising animmediate release phase and a slow release phase; the immediate releasephase comprising all the potassium clavulanate and a first part ofamoxycillin, with a pharmaceutically acceptable carrier or excipient;and the slow release phase comprising a second part of amoxycillinformulated with a release modifying pharmaceutically acceptableexcipient.
 24. The modified release formulation according to claim 23 inwhich the ratio of amoxycillin and potassium clavulanate is 14:1 to16:1.
 25. The modified release formulation according to claim 23 whichhas a biphasic profile with respect to amoxycillin.
 26. The modifiedrelease formulation according to claim 23 which has an AUC value whichis at least 80% of that of the corresponding dosage of amoxycillin takenas a conventional (immediate release) tablet(s), over the same dosageperiod.
 27. The modified release formulation according claim 23 in whichthe ratio of amoxycillin in the immediate and slow release phases isfrom 3:1 to 1:3.
 28. The modified release formulation according claim 23comprising a unit dosage form in the range 700 to 1300 mg amoxycillin or1400 to 2600 mg and a corresponding amount of potassium clavulanate. 29.The modified release formulation according to claim 28 in which the unitdosage is: 1000, 875 or 750 mg ±5% amoxycillin and 62.5 mg ±5% potassiumclavulanate; or 2000, 1750 or 1500 mg ±5% amoxycillin and 125 mg ±5%potassium clavulanate; in a nominal ratio of about 16:1, 14:1 or 12:1,respectively, in combination with a pharmaceutically acceptableexcipient or carrier.
 30. The modified release formulation according toclaim 29 in the form of a tablet.
 31. The modified release formulationaccording to claim 30 comprising 1000 mg ±5% amoxycillin and 62.5 mg ±5%potassium clavulanate, in a nominal ratio of about 16:1; and in whichthe immediate release phase comprises about 563 mg ±5% amoxycillin andabout 62.5 mg ±5% of potassium clavulanate, and the slow release phasecomprises about 438 mg ±5% of amoxycillin.
 32. The modified releaseformulation according to claim 23 in which the amoxycillin of the slowrelease phase consists essentially of crystallised sodium amoxycillin.33. The modified release formulation according to claim 23 which is alayered tablet and in which the immediate and slow release phases areprovided for as separate layers of the layered tablet.
 34. The layeredtablet according to claim 33 in which the slow release layer furthercomprises a release retarding excipient which is selected from a pHsensitive polymer, a release-retarding polymer which has a high degreeof swelling in contact with water or aqueous media, a polymeric materialwhich forms a gel on contact with water or aqueous media, a polymericmaterial which has both swelling and gelling characteristics in contactwith water or aqueous media, or mixtures thereof.
 35. The layered tabletaccording to claim 34 in which the release retarding gellable polymer isselected from methylcellulose, carboxymethylcellulose, low-molecularweight hydroxypropylmethylcellulose, low-molecular weightpolyvinylalcohols, polyoxyethyleneglycols, non-cross linkedpolyvinylpyrrolidone, or xanthan gum.
 36. The layered tablet accordingto claim 34 in which the release retarding excipient is xanthan gum. 37.The layered tablet according to claim 36 in which the xanthan gum ispresent in from 1 to 25% by weight of the layer.
 38. The layered tabletaccording to claim 33 in which the slow release layer comprises fromabout 70 to 80% of amoxycillin, from about 1 to 25% of xanthan gum, fromabout 10 to 20% of fillers and/or compression agents, and a conventionalquantity of a lubricant.
 39. The layered tablet according to claim 33 inwhich the slow release phase comprises sodium amoxycillin and in whichthe slow release layer comprises a pharmaceutically acceptable organicacid present in a molar ratio of from 100:1 to 1:10 (amoxycillin salt toorganic acid).
 40. The layered tablet according to claim 39 in which thepharmaceutically acceptable acid is citric acid present in a molar ratioof about 50:1 to 1:2.
 41. The layered tablet according to claim 40further comprising a release retarding gellable polymer.
 42. The layeredtablet according to claim 41 in which the release retarding gellablepolymer is xanthan gum.
 43. The layered tablet according to claim 42 inwhich xanthan gum is present in from 0.5 to 8% by weight of the slowrelease layer.
 44. The layered tablet according to claim 33 comprisingin total about 700 to 1250 mg amoxycillin and a pro rata amount ofpotassium clavulanate, in a nominal ratio of about 16:1, 14:1 or 12:1,respectively, in combination with a pharmaceutically acceptableexcipient or carrier.
 45. The layered tablet according to claim 39 whichcomprises in the immediate release layer about 1000 mg ±5% ofamoxycillin and 62.5 mg ±5% of potassium clavulanate, and in the slowrelease layer about 438 mg ±5% of crystallised sodium amoxycillin, about78 mg ±10% of citric acid and about 2% by weight of xanthan gum.
 46. Themodified release formulation according to claim 23 in which theimmediate release phase is formed from immediate release granulescomprising amoxycillin and potassium clavulanate; or immediate releasegranules comprising amoxycillin and potassium clavulanate admixed with afurther immediate release granule comprising amoxycillin and the slowrelease phase is formed from slow release granules comprisingamoxycillin.
 47. The modified release formulation according to claim 46which is formulated as a unit dose sachet, capsule, monolith tablet,dispersible tablet, chewable tablet, effervescent chewable tablet, or aeffervescent dispersible tablet.
 48. A pharmaceutical formulationcomprising 1000 mg ±5% amoxycillin and 62.5 mg ±5% potassium clavulanicacid, in a nominal ratio of about 16:1, in combination with apharmaceutically acceptable excipient or carrier.
 49. The pharmaceuticalformulation according to claim 48 in which the amoxycillin is present asa mixture of amoxycillin trihydrate and sodium amoxycillin in a ratio of3:1 to 1:3.
 50. A pharmaceutical formulation comprising amoxycillin andpotassium clavulanate in a ratio of from 1:1 to 30:1 in whichamoxycillin is provided as a mixture of amoxycillin trihydrate andsodium amoxycillin in a ratio of from 3:1 to 1:3.
 51. The pharmaceuticalformulation according to claim 50 in which the ratio of amoxycillintrihydrate and sodium amoxycillin is from 3:2 to 2:3.
 52. Apharmaceutical formulation comprising a pharmaceutically acceptablesoluble salt of amoxycillin in a slow release phase which furthercomprises a release retarding excipient which is a pharmaceuticallyacceptable organic acid present in a molar ratio of from 100:1 to 1:10(amoxycillin salt to organic acid).
 53. The pharmaceutical formulationaccording to claim 52 in which the molar ratio is 50:1 to 1:5.
 54. Thepharmaceutical formulation according to claim 52 in which the organicacid is citric acid.
 55. The pharmaceutical formulation according toclaim 52 in which the soluble salt of amoxycillin is sodium amoxycillin.56. A kit comprising an immediate release formulation comprisingamoxycillin and potassium clavulanate, optionally with a conventional(immediate release) formulation comprising amoxycillin and a slowrelease formulation comprising amoxycillin (and no potassiumclavulanate).
 57. A slow release pharmaceutical formulation comprisingamoxycillin (as the sole active ingredient) formulated with a releaseretarding excipient which causes a slow release of the amoxycillin fromthe formulation, and excluding tablets which comprise from 400 to 500 mgamoxycillin trihydrate or a mixture comprising at least 70% amoxycillintrihydrate and up to 30% sodium amoxycillin andhydroxypropylmethylcellulose.
 58. The pharmaceutical formulationaccording to claim 57 which comprises 100 to 1250 mg amoxycillin.
 59. Apharmaceutical formulation according to claim 57 in which the releaseretarding excipient is xanthan gum.
 60. A pharmaceutical formulationaccording to claim 59 in which the xanthan gum is pharmaceutical gradexanthan gum, 200 mesh.
 61. A pharmaceutical formulation according toclaim 59 in which the xanthan gum is present in from about 0.5 to 25% byweight.
 62. Compacted granules for use in a pharmaceutical formulationcomprising amoxycillin a diluent or compression aid, and an organic acid(if amoxycillin is present as a soluble salt thereof), or releaseretarding polymer, or a mixture thereof.
 63. Compacted granules for usein a pharmaceutical formulation comprising sodium amoxycillin,microcrystalline cellulose, and an organic acid or a release retardingpolymer or a mixture thereof.
 64. A process for preparing compactedgranules according to 63 which process comprises the steps of blendingtogether sodium amoxycillin, microcrystalline cellulose, and organicacid or release retarding polymer or mixture thereof, compacting theblend and then milling.
 65. The pharmaceutical formulation according toclaim 46 comprising slow release compacted granules comprisingamoxycillin, a diluent/compression aid, and an organic acid (ifamoxycillin is present as a soluble salt thereof) or a release retardingpolymer or a mixture thereof, and immediate release compacted granulescomprising amoxycillin and potassium clavulanate or immediate releasecompacted granules comprising amoxycillin and potassium clavulanate, andfurther immediate release compacted granules comprising amoxycillin. 66.A formulation according to claim 23 having an AUC, C_(max) and t_(max)substantially according to FIG. 5 (formulation VI or VII).
 67. Aformulation which is bioequivalent to the formulation of claim 66.